DOCSLIB.ORG

Human Genetics Lecture #1 March 25, 2014

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Human Genetics Lecture #1 March 25, 2014 Bio 5491 - Advanced Genetics Human Genetics Lecture #1 March 25, 2014 Cristina de Guzman Strong, Ph.D. Department of Medicine Dermatology/Pharmacogenomics McDonnell Basic Sciences 770 [email protected] 362-7695 Human Genetics • Karyotype • Mutations in Regulatory • Genetic Variants Elements • Mendelian Diseases • Copy number variation • Linkage, positional cloning diseases • Penetrance/Expressivity • Mitochondrial genetics • Human Genome Project • Human-specific variation • GWAS/Next-Gen • Future sequencing (Exome) • Undiagnosed Diseases • Epigenetics/ENCODE What is Human Genetics? The relationship between natural DNA sequence variation(s) and human phenotypic traits What is different about Human Genetics? • Imprinting……..uniquely mammalian. • Trinucleotide repeat diseases…….anticipation. • One can study complex behaviours and cognition. • Extensive sequence variation leads to common/ complex disease 1. Common disease – common variant hypothesis 2. Large # of small-effect variants 3. Large # of large-effect rare variants 4. Combo of genotypic, environmental, epigenetic interactions Greg Gibson, Nature Review Gen 2012 Human Genome (Karyotype) 22 autosomes/ XY sex chromosomes 02_13.jpg Human genome is ~41% GC, but that is non-randomly distributed. Dark G-bands are lower GC (and lower gene content) Genetic variation: Single Base Pair C T – SNP (single nucleotide polymorphism) - Freq > 0.01 – Can also be 1 insertion or 1 deletion, “indel” – Alleles with Freq < 0.01 – called rare variants OR SNPs – Mutations: usually, really RARE. Alter protein function or regulation. Simple Mendelian Trait. Can cause disease Understanding the SNP Major vs. Minor Allele • Referring to coding OR non-coding region • Nomenclature – rs”X” (SNP), can also be indel Looking up a SNP C T Looking up a SNP C T Types of Coding Mutations K867X K867R K867T Courtesy of Laura Elnitski Example of Nomenclature (NF1) Ars et al., HMG 2000 Resource for Sequence Variant Calling • http://www.hgvs.org/mutnomen/recs.html Genetic Variation: Copy Number Insertion/deletions of small number of bp (indels): – Polymorphism - also known as copy number variation (CNV) – Indels in coding region – frameshift mutation if less than 3 bp – Repeat sequences: di (TG), tri, or tetra – microsatellites Larger repeats: VNTRs (variable number of tandem repeats), minisatellites - used for forensics Deletions or duplications of larger blocks of DNA encompassing one or more genes (Williams or DiGeorge Syndrome) Genetic Variation: Copy Number Larger repeats: VNTRs (variable number of tandem repeats), minisatellites - used for forensics Description of diseases and mutations • Online Mendelian Inheritance in Man (McKusick): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? db=OMIM Human mutation database : http://www.hgmd.org Characteristics of Simple/ Mendelian diseases • >20,000 Mendelian traits described in OMIM (Online Mendelian Inheritance in Man) • Freq usually < 1/10,000 • Most mutations: Loss of function and recessive phenotypes, e.g. inborn errors of metabolism • Dominant mutations: Cause disease due to 50% of protein product (haploinsufficiency) or dominant negative effect • Some dominant mutations lead to “gain of function” - e.g. expanded polyglutamine repeat leading to abnormal aggregate (triplet repeat diseases) Thompson & Thompson, Genetics in Medicine (5th) Basic Mendelian pedigree patterns 04_02.jpg Example of Mendelian disorder: Waardenburg Syndrome (PAX3: Deafness in association with pigmentary anomalies and defects of neural crest-derived tissues). Loss of function mutations in PAX3 gene: Type 1 Waardenburg syndrome 16_01.jpg Variable penetrance versus variable expressivity Penetrance - the frequency of expression of an allele when it is present in the genotype of the organism Example: if 9/10 of individuals carrying an allele express the trait, the trait is said to be 90% penetrant Expressivity - variation in allelic expression when the allele is penetrant. Example: For polydactyly, an extra digit may occur on one or more appendages, and the digit can be full size or just a stub. Modifier genes can affect penetrance, dominance, expressivity Neurofibromatosis ( NF1) • Mutations in neurofibromin gene • Reduced penetrance • Wide range of symptoms – variable expressivity Nature 455, 1061-1068(23 October 2008) Cloning of Genes for Simple Mendelian Traits where the biochemical defect is not known Linkage (to locate chromosomal region), followed by positional cloning Standard of Proof for Positional Cloning For fully penetrant, simple Mendelian traits one usually detects obviously deleterious mutations in coding regions for multiple alleles. Positional Cloning 14_02.jpg Characteristics of families for Linkage Analysis Large number of affected members required (generally > 10): Single large families where LOD of theta > 3 OR Multiple small families: Add LOD scores at different theta values to obtain LOD > 3 Example of positional cloning: Huntington’s disease Dominantly inherited Fatal presenile dementia. Symptoms include spasmodic jerking of the limbs, psychotic behavior, and mental deterioration. First described by George Huntington in 1872. Incidence is 5-10/100,000. Genetic linkage to chr 4: 1984: Nancy Wexler, Jim Gusella . 1983 - Linkage to G8 (also called D4S10) Mapped approximately 4 cM from the HD locus. 10 more years to clone the HD to clone gene. Huntingtin gene - HTT Haplotype analysis 14_04.jpg How did we get here? • ~1,200 “simple” Mendelian trait loci have been cloned, mostly by genetic linkage analysis and positional cloning. • The revolution in human genetics has been driven by advances in genomics, DNA sequencing and polymorphism detection. Courtesy of Eric Green Courtesy of Eric Green Post HGP 1000 Genomes Project sequence about 2,000 unidentified individuals from 20 populations around the world Capture minor allele frequencies as low as 1% Post HGP Published Genome-Wide Associations through 12/2012 Published GWA at p≤5X10-8 for 17 trait categories NHGRI GWA Catalog www.genome.gov/GWAStudies www.ebi.ac.uk/fgpt/gwas/ 1% of the genome – 30Mb From Nimblegen Slide courtesy of Elliott Margulies Exome sequencing – XIAP Whole Bone Marrow Transplant January 2010 Slide courtesy of Eric Green Slide courtesy of Eric Green (modified) Slide courtesy of Eric Green Slide courtesy of Eric Green Hon, Hawkins, Ren review (Human Molecular Genetics 2009) !"!#$ • %&'()*+,-$ ./012345$*)',$6/77$ • 8&9*&:3-$ ./0123;$ • <3=-3'',->$<3:-(?+$.@A!$ .30123/$ • 6-,2,+3-5$+-?+9,-*B$C,=3&$:9-,2*+?&D$ ./0E*:$ ./0E234$ • A:+?F*+3G$ ./0;H*:$ ./0;H23/$ • "-*&':-?=+?,&*)$3),&I*+?,&>$ • J?)3&:?&I$C6)*+95$J:?3&:3$;77/D$K$'?)3&:?&I$,L$+93$M$:9-,2,',235$6!N$+,$ +-?23+9O)*+3$./0;H$ ./0/P23/$ • A:+?F*+3G$ .10;7234$ 6,);CQD$ $ ./R/S.;ART$2*-U$G,(Q)3$F*-?*&+$&(:)3,',23$+9*+$*-3$(&'+*Q)3$*&G$2*-U$ &(:)3,',23VL-33$-3I?,&'$?&$*:+?F3$=-,2,+3-'$*&G$-3I()*+,-O$-3I?,&'$ $ http://www.nature.com/encode/#/threads Maher, Nature 2012 Mutations in regulatory regions – Altered TF binding to promoter or enhancer e.g. sonic hedgehog enhancer – Splice site alterations (e.g. some beta thalassemias) – Altered mRNA stability (e.g. in AAUAA) – Altered micro RNA binding leading to altered protein translation Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 2005, 310. Nature March 23 2011 Advance issue Copy Number (Structural) Variation Structural variation of the genome kilobase- to megabase-sized deletions, duplications, insertions, Inversions complex combinations of rearrangements. CNVs due do non-allelic recombination between low-copy repeats (LCRs) that lead to human disease 11_19_2.jpg (Smith-Magenis syndrome) DiGeorge Syndrome Velocardiofacial syndrome Examples of contiguous gene syndromes • Xp: – Successively large deletions remove more genes and add more diseases • 11p12: – WAGR (Wilm’s tumor, Aniridia, Genital and/or urinary tract abnormalities, Mental retardation) Segmental aneuploidy • Phenotype in heterozygotes depends on only a subset of deleted genes that are dosage sensitive • De Novo microdeletions, frequently flanked by long repeats (often transcribed hence open chromatin - more recombination prone) 46, 5p- Adapted from Figure © 2010 PJ Russell, iGenetics 3rd ed. Williams syndrome - example of segmental aneuploidy (1.6Mb deletion at 7q11.23/~ 20 genes) 1/20,000 births Growth retardation Hypercalcemia Sypervalvular aortic stenosis (elastin) Moderately mentally retarded Highly sociable, often musical, defect in visuospatial constructive ability Deletions identified in Williams syndrome Current knowledge of of CNV (copy number variation) in the human genome http://projects.tcag.ca/variation/ 011/10: Total entries: 101,923 (hg18) CNVs: 66,741 Inversions: 953 InDels (100bp-1Kb): 34,229 Total CNV loci: 15,963 Articles cited: 42 CNV afecting one human phenotype: Ability to digest starch: Diet and the evolution of human amylase gene copy number variation Perry et al. Nature Genet. Nature Genetics 39, 1256 - 1260 (2007) Different types of mechanisms leading to SVs/CNVs • Non-allelic homologous recombination (NAHR) • Non homologous end joining (NHEJ) • Transposon insertion (e.g. L1) Gu et al. PathoGenetics 2008 1:4 Genomic rearrangements in the genome are likely to be more common than expected 5% of human genes are found in interspersed duplicated copies Recent examples of large rearrangement polymorphisms in the human genome • Sebat et al. Large-scale copy number polymorphism in the human genome. Science 305:525-8 (2004) • A common inversion under selection in Europeans Stefansson et al.
Load more

Recommended publications
  • (Lcrs) in 22Q11 Mediate Deletions, Duplications, Translocations, and Genomic Instability: an Update and Literature Review Tamim H
    review January/February 2001 ⅐ Vol. 3 ⅐ No. 1 Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: An update and literature review Tamim H. Shaikh, PhD1, Hiroki Kurahashi, MD, PhD1, and Beverly S. Emanuel, PhD1,2 Several constitutional rearrangements, including deletions, duplications, and translocations, are associated with 22q11.2. These rearrangements give rise to a variety of genomic disorders, including DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes (DGS/VCFS/CAFS), cat eye syndrome (CES), and the supernumerary der(22)t(11;22) syndrome associated with the recurrent t(11;22). Chromosome 22-specific duplications or low copy repeats (LCRs) have been directly implicated in the chromosomal rearrangements associated with 22q11.2. Extensive sequence analysis of the different copies of 22q11 LCRs suggests a complex organization. Examination of their evolutionary origin suggests that the duplications in 22q11.2 may predate the divergence of New World monkeys 40 million years ago. Based on the current data, a number of models are proposed to explain the LCR-mediated constitutional rearrangements of 22q11.2. Genetics in Medicine, 2001:3(1):6–13. Key Words: duplication, evolution, 22q11, deletion and translocation Although chromosome 22 represents only 2% of the haploid The 22q11.2 deletion syndrome, which includes DGS/ human genome,1 recurrent, clinically significant, acquired, VCFS/CAFS, is the most common microdeletion syndrome. and somatic
    [Show full text]
  • Copy Number Variation and Huntington's Disease
    UNIVERSIDADE DE LISBOA FACULDADE DE MEDICINA DE LISBOA Copy number variation and Huntington’s disease Angelica Vittori Ramo das Ciências Biomédicas Especialidade – Neurociências Outubro 2013 UNIVERSIDADE DE LISBOA FACULDADE DE MEDICINA DE LISBOA Copy number variation and Huntington’s disease Candidata: Angelica Vittori Orientadores: Prof . Doutor Tiago Fleming Outeiro Doutor Flaviano Giorgini Doutor Edward J. Hollox Ramo das Ciências Biomédicas Especialidade – Neurociências Todas as afirmações efectuadas no presente documento são da exclusiva II responsabilidade do seu autor, não cabendo qualquer responsabilidade à faculdade de medicina de lisboa pelos conteúdos nela apresentados. A impressão são da exclusiva está dissertação foi aprovada pelo Conselho Cientifico da Faculdade de Medicina em reunião de 19 de Novembro de 2013. III Resumo A variação de número de cópias (CNV em inglês) é uma modificação de uma sequência de DNA que apresenta uma inserção ou deleção em comparação com um genoma de referência com um número de cópias de N = 2. Com um comprimento variável, desde 50 pares de bases até várias megabases, as CNVs identificadas têm um tamanho médio de ~ 3 Kb e representam cerca de 4% do genoma humano. As CNVs, como outras variações genéticas, podem afetar directamente os níveis de expressão dos genes afectados. Os efeitos indirectos na expressão genética podem ser causados por alterações da posição, interrompendo o quadro de leitura do gene ou posteriormente, perturbando as redes de regulação genética. Foi demonstrado que as CNVs são em grande parte responsáveis pela evolução humana e diversidade genética entre os indivíduos. A relevância das CNVs no genoma humano foi salientada por vários estudos de associação que mostraram o efeito das CNVs na susceptibilidade a doenças neurodegenerativas, doenças de características complexas, e por serem a principal causa do aparecimento de doenças mendelianas ou por conferirem um fenótipo benigno.
    [Show full text]
  • Gentles Et Al 2007 Gen Res.Pdf
    Downloaded from www.genome.org on July 2, 2007 Letter Evolutionary dynamics of transposable elements in the short-tailed opossum Monodelphis domestica Andrew J. Gentles,1,2,6 Matthew J. Wakefield,3 Oleksiy Kohany,2 Wanjun Gu,4 Mark A. Batzer,5 David D. Pollock,4 and Jerzy Jurka2,6 1Department of Radiology, School of Medicine, Stanford University, Stanford, California 94305, USA; 2Genetic Information Research Institute, Mountain View, California 94043, USA; 3ARC Centre for Kangaroo Genomics, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia; 4Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora 80045, Colorado, USA; 5Department of Biological Sciences, Biological Computation and Visualization Center, Center for BioModular Multi-Scale Systems, Louisiana State University, Baton Rouge, Louisiana 70803, USA The genome of the gray short-tailed opossum Monodelphis domestica is notable for its large size (∼3.6 Gb). We characterized nearly 500 families of interspersed repeats from the Monodelphis. They cover ∼52% of the genome, higher than in any other amniotic lineage studied to date, and may account for the unusually large genome size. In comparison to other mammals, Monodelphis is significantly rich in non-LTR retrotransposons from the LINE-1, CR1, and RTE families, with >29% of the genome sequence comprised of copies of these elements. Monodelphis has at least four families of RTE, and we report support for horizontal transfer of this non-LTR retrotransposon. In addition to short interspersed elements (SINEs) mobilized by L1, we found several families of SINEs that appear to use RTE elements for mobilization. In contrast to L1-mobilized SINEs, the RTE-mobilized SINEs in Monodelphis appear to shift from G+C-rich to G+C-low regions with time.
    [Show full text]
  • Repetitive Elements in Humans
    International Journal of Molecular Sciences Review Repetitive Elements in Humans Thomas Liehr Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, D-07747 Jena, Germany; [email protected] Abstract: Repetitive DNA in humans is still widely considered to be meaningless, and variations within this part of the genome are generally considered to be harmless to the carrier. In contrast, for euchromatic variation, one becomes more careful in classifying inter-individual differences as meaningless and rather tends to see them as possible influencers of the so-called ‘genetic background’, being able to at least potentially influence disease susceptibilities. Here, the known ‘bad boys’ among repetitive DNAs are reviewed. Variable numbers of tandem repeats (VNTRs = micro- and minisatellites), small-scale repetitive elements (SSREs) and even chromosomal heteromorphisms (CHs) may therefore have direct or indirect influences on human diseases and susceptibilities. Summarizing this specific aspect here for the first time should contribute to stimulating more research on human repetitive DNA. It should also become clear that these kinds of studies must be done at all available levels of resolution, i.e., from the base pair to chromosomal level and, importantly, the epigenetic level, as well. Keywords: variable numbers of tandem repeats (VNTRs); microsatellites; minisatellites; small-scale repetitive elements (SSREs); chromosomal heteromorphisms (CHs); higher-order repeat (HOR); retroviral DNA 1. Introduction Citation: Liehr, T. Repetitive In humans, like in other higher species, the genome of one individual never looks 100% Elements in Humans. Int. J. Mol. Sci. alike to another one [1], even among those of the same gender or between monozygotic 2021, 22, 2072.
    [Show full text]
  • Recent Advance in Our Understanding of the Molecular Nature of Chromosomal Abnormalities
    Journal of Human Genetics (2009) 54, 253–260 & 2009 The Japan Society of Human Genetics All rights reserved 1434-5161/09 $32.00 www.nature.com/jhg REVIEW Recent advance in our understanding of the molecular nature of chromosomal abnormalities Hiroki Kurahashi, Hasbaira Bolor, Takema Kato, Hiroshi Kogo, Makiko Tsutsumi, Hidehito Inagaki and Tamae Ohye The completion of the human genome project has enabled researchers to characterize the breakpoints for various chromosomal structural abnormalities including deletions, duplications or translocations. This in turn has shed new light on the molecular mechanisms underlying the onset of gross chromosomal rearrangements. On the other hand, advances in genetic manipulation technologies for various model organisms has increased our knowledge of meiotic chromosome segregation, errors which, contribute to chromosomal aneuploidy. This review focuses on the current understanding of germ line chromosomal abnormalities and provides an overview of the mechanisms involved. We refer to our own recent data and those of others to illustrate some of the new paradigms that have arisen in this field. We also discuss some perspectives on the sexual dimorphism of some of the pathways that leads to these chromosomal abnormalities. Journal of Human Genetics (2009) 54, 253–260; doi:10.1038/jhg.2009.35; published online 17 April 2009 Keywords: aneuploidy; cruciform; deletion; gross chromosomal rearrangement; low-copy repeat; non-disjunction; palindrome; translocation THE RANDOM NATURE OF GROSS CHROMOSOMAL inverted repeats and the critical break points often reside within these REARRANGEMENTS regions. When a DSB occurs within one copy of a repeat segment, The development of chromosomal structural abnormalities, also illegitimate DSB repair through the HR pathway using another copy of known as gross chromosomal rearrangements (GCR), is essentially the repeat segments may be induced, and this is the most likely dependent on two distinct processes: double-strand breaks (DSB) and mechanism of recurrent GCR.
    [Show full text]
  • Novel Methods to Study Genomic Fragility and Structural Variation
    From the Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden NOVEL METHODS TO STUDY GENOMIC FRAGILITY AND STRUCTURAL VARIATION Reza Mirzazadeh Stockholm 2019 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Arkitektkopia AB, 2019 © Reza Mirzazadeh, 2019 ISBN 978-91-7831-615-1 Novel methods to study genomic fragility and structural variation THESIS FOR DOCTORAL DEGREE (Ph.D.) Defended at Karolinska Institutet, Biomedicum seminar room 1, Solnavägen 9, Stockholm. December 6th 2019, at 10:00 a.m. By Reza Mirzazadeh Principal Supervisor: Opponent: Assistant Professor Nicola Crosetto Assistant Professor Vicente Pelechano Karolinska Institutet Karolinska Institutet Department of Medical Biochemistry Department of Microbiology, and Biophysics Tumor and Cell Biology Co-supervisor(s): Examination Board: Associate Professor Theodoros Foukakis Professor Ulf Landegren Karolinska Institutet Uppsala University Department of Oncology-Pathology Department of Immunology, Genetics and Pathology Professor Qiang Pan-Hammarström Karolinska Institutet Professor Mattias Mannervik Department of Biosciences and Nutrition Stockholm University Department of Molecular Biosciences, The Wenner-Gren Institute Professor Richard Rosenquist Brandell Karolinska Institutet Department of Molecular Medicine and Surgery Dedicated to family, friends, colleagues, my wonderful wife, Nana, and my amazing daughter Elsa, for their support and love. ABSTRACT DNA double-strand breaks (DSBs) are major DNA lesions that when repaired unfaithfully can give rise to loss of genetic information, chromosomal rearrange- ments such as insertions/deletions (indels) and copy number alterations (CNAs), which in turn lead to genomic instability that is characteristic of almost all cancer types. In this context, it is thought that genomic instability has critical roles in cancer initiation, progression and intra-tumor heterogeneity (ITH).
    [Show full text]
  • The 22Q11 Low Copy Repeats Are Characterized by Unprecedented Size and Structural Variability
    Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Research The 22q11 low copy repeats are characterized by unprecedented size and structural variability Wolfram Demaerel,1,10 Yulia Mostovoy,2,10 Feyza Yilmaz,3,4,10 Lisanne Vervoort,1 Steven Pastor,5 Matthew S. Hestand,1,6,7 Ann Swillen,1 Elfi Vergaelen,1 Elizabeth A. Geiger,4 Curtis R. Coughlin,4 Stephen K. Chow,2 Donna McDonald-McGinn,5 Bernice Morrow,8 Pui-Yan Kwok,2 Ming Xiao,9 Beverly S. Emanuel,5 Tamim H. Shaikh,4 and Joris R. Vermeesch1 1Departement of Human Genetics, KU Leuven, Leuven, 3000 Belgium; 2Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, California 94158, USA; 3Department of Integrative Biology, University of Colorado Denver, Denver, Colorado 80204, USA; 4Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado 80045, USA; 5Division of Human Genetics, Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 6Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA; 7Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45221, USA; 8Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA; 9School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evo- lution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved.
    [Show full text]
  • Non-Hotspot-Related Breakpoints of Common Deletions In
    1of8 ELECTRONIC LETTER Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions R Visser, O Shimokawa, N Harada, N Niikawa, N Matsumoto ............................................................................................................................... J Med Genet 2005;42:e (http://www.jmedgenet.com/cgi/content/full/42/11/e66). doi: 10.1136/jmg.2005.034355 recently confirmed by others.12 Similar analysis at a nucleo- Background: Sotos syndrome (SoS) is a disorder charac- tide level of recombination hotspots in other genomic terised by excessive growth, typical craniofacial features, disorders has identified, among others, regions of unin- and developmental retardation. It is caused by haploinsuf- terrupted sequence homology, several sequence motifs, and fiency of NSD1 at 5q35. There is a 3.0 kb recombination raised GC content as hotspot features.11 13–16 However, these hotspot in which the breakpoints of around 80% of SoS features are not consistent for all hotspots and, owing to the patients with a common deletion can be mapped. analytically difficult background of highly homologous LCRs, Objective: To identify deletion breakpoints located outside the number of identified hotspot related and non-hotspot- the SoS recombination hotspot. related breakpoints is limited. Other possible contributing Methods: A screening system for the directly orientated factors—such as epigenetic alterations or specific chromatin segments of the SoS LCRs was developed for 10 SoS patients structure—have been suggested.17 Interestingly, breakpoints with a common deletion who were negative for the SoS of gross deletions were indeed found to coincide with non-B 18 hotspot. Deletion-junction fragments were analysed for DNA DNA conformations. Non-B DNA conformation could result duplex stability and their relation to scaffold/matrix attach- in an increase in accessibility for cleavage enzymes or a 18 ment regions (S/MARs).
    [Show full text]
  • Disorders of the Genome Architecture: a Review
    Genomic Med. (2008) 2:69–76 DOI 10.1007/s11568-009-9028-2 REVIEW ARTICLE Disorders of the genome architecture: a review Dhavendra Kumar Received: 22 July 2008 / Revised: 17 December 2008 / Accepted: 13 February 2009 / Published online: 11 March 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Genetic diseases are recognized to be one of hotspots in male-germ cells indicate an excess of genomic the major categories of human disease. Traditionally rearrangements resulting in microduplications that are genetic diseases are subdivided into chromosomal clinically underdiagnosed compared to microdeletion syn- (numerical or structural aberrations), monogenic or Men- dromes. Widespread application of high-resolution genome delian diseases, multifactorial/polygenic complex diseases analyses may offer to detect more sporadic phenotypes and mitochondrial genetic disorders. A large proportion of resulting from genomic rearrangements involving de novo these conditions occur sporadically. With the advent of copy number variation. newer molecular techniques, a number of new disorders and dysmorphic syndromes are delineated in detail. Some Keywords Genome Á Genome architecture Á of these conditions do not conform to the conventional Genomic disorder Á Genomic rearrangements Á inheritance patterns and mechanisms are often complex Mendelian disease Á Sporadic disease Á De novo mutations Á and unique. Examples include submicroscopic microdele- Malformation syndrome tions or microduplications, trinucleotide repeat disorders, epigenetic disorders
    [Show full text]
  • Structural Features of the Genome Can Lead to DNA Rearrangements And
    REVIEWS Genomic disorders: Structural characteristics of the human genome predis- pose to rearrangements that result in human disease structural features of the traits. The gene is still the key in mediating the pheno- type, but is altered almost coincidentally by the rearrangement. I will refer to such conditions that result genome can lead to DNA from genome architecture as genomic disorders. Genomic disorders are caused by an alteration of the genome that might lead to the complete loss or gain of rearrangements and a gene(s) sensitive to a dosage effect or, alternatively, might disrupt the structural integrity of a gene. This human disease traits mechanism is in sharp contrast to the classical mecha- nism for genetic disease, by which an abnormal pheno- type is primarily a result of point mutation. Genome JAMES R. LUPSKI ([email protected]) alterations can occur through many mechanisms, one of which is homologous recombination during meiosis Molecular medicine began with Pauling’s seminal work, between region-specific, low-copy repeated sequences. which recognized sickle-cell anemia as a molecular These homologous recombination events result in disease, and with Ingram’s demonstration of a specific a type of DNA rearrangement that is a function of the chemical difference between the hemoglobins of normal orientation of the repeated sequences that act as and sickled human red blood cells. During the four 1 substrates for homologous recombination . Recom- decades that followed, investigations have focused on the bination between direct repeats can lead to deletion gene – how mutations specifically alter DNA and how these and/or duplication of the genetic material between the changes affect the structure and expression of encoded repeats, while recombination between inverted repeats proteins.
    [Show full text]
  • An Overview of Duplicated Gene Detection Methods: Why the Duplication Mechanism Has to Be Accounted for in Their Choice
    G C A T T A C G G C A T genes Review An Overview of Duplicated Gene Detection Methods: Why the Duplication Mechanism Has to Be Accounted for in Their Choice 1, 1, 1 2 Tanguy Lallemand y , Martin Leduc y, Claudine Landès , Carène Rizzon and Emmanuelle Lerat 3,* 1 IRHS, Agrocampus-Ouest, INRAE, Université d’Angers, SFR 4207 QuaSaV, 49071 Beaucouzé, France; [email protected] (T.L.); [email protected] (M.L.); [email protected] (C.L.) 2 Laboratoire de Mathématiques et Modélisation d’Evry (LaMME), Université d’Evry Val d’Essonne, Université Paris-Saclay, UMR CNRS 8071, ENSIIE, USC INRAE, 23 bvd de France, CEDEX, 91037 Evry Paris, France; [email protected] 3 Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France * Correspondence: [email protected]; Tel.: +3342432918 These authors contributed equally to this work. y Received: 30 July 2020; Accepted: 2 September 2020; Published: 4 September 2020 Abstract: Gene duplication is an important evolutionary mechanism allowing to provide new genetic material and thus opportunities to acquire new gene functions for an organism, with major implications such as speciation events. Various processes are known to allow a gene to be duplicated and different models explain how duplicated genes can be maintained in genomes. Due to their particular importance, the identification of duplicated genes is essential when studying genome evolution but it can still be a challenge due to the various fates duplicated genes can encounter. In this review, we first describe the evolutionary processes allowing the formation of duplicated genes but also describe the various bioinformatic approaches that can be used to identify them in genome sequences.
    [Show full text]
  • Recombination Hot Spots and Human Disease Smita M
    Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Recombination Hot Spots and Human Disease Smita M. Purandare1 and Pragna I. Patel1–4 Departments of 1Neurology, 2Molecular and Human Genetics and 3Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030 Recombination between homologous DNA se- phic VNTRs (variable number tandem repeats) or quences occurs in all organisms, and the resultant hypervariable minisatellite DNA, where the size of exchange of information is critical for the survival the repeat unit ranges from 9 to 24 bp. VNTRs have of species. Recombination is an essential cellular been shown to be hot spots for homologous recom- process catalyzed by proteins explicitly expressed bination in human cells (Wahls et al. 1990). Micro- for this purpose. It provides an effective means of satellite DNA consists of small arrays of tandem re- generating genetic diversity that is important for peats (usually 1–4 bp units) that are interspersed evolution. The proteins involved in recombination throughout the genome, in blocks consisting of allow cells to retrieve sequences lost when DNA is <150 bp. damaged by radiation or chemicals, by replacing the In contrast to tandemly repeated DNA, inter- damaged section with an undamaged strand from a spersed repetitive DNA consists of repeat units dis- homologous chromosome. The process of homolo- persed throughout the genome. Based on the repeat gous recombination has also been used to study unit length, two major classes are recognized: short gene function by way of gene knockouts. However, interspersed nuclear elements [(SINES) e.g., the Alu recombination and factors involved in recombina- repeat family] and long interspersed nuclear ele- tion may also be a source of harmful mutations and ments [(LINES) e.g., the LINE-1 or L1 element disease.
    [Show full text]